Talk abstracts

Talk on Wednesday 04:45-05:00pm submitted by Douglas Cheung

Targeting CDKs with PHA-8481125 in estrogen receptor negative breast cancer

Douglas G. Cheung (Department of Molecular Immunology, Virology and Medical Genetics, Ohio State University, Columbus, OH 43210, USA), Gianpiero Di Leva (Department of Molecular Immunology, Virology and Medical Genetics, Ohio State University, Columbus, OH 43210, USA), Matteo Fassan (ARC-NET Research Centre, University and Hospital Trust of Verona, Verona, VR 37010, Italy), Arpan Kumar, Krishna Patel, Dorothee Wernicke, Stefano Volinia (Department of Molecular Immunology, Virology and Medical Genetics, Ohio State University, Columbus, OH 43210, USA), Marina Ciomei (Business Unit Oncology, Nerviano Medical Sciences, Nerviano, MI 20014, Italy), Carlo M. Croce (Department of Molecular Immunology, Virology and Medical Genetics, Ohio State University, Columbus, OH 43210, USA)

Abstract:
The cell cycle is frequently dysregulated in breast cancer, leading to uncontrolled division of cells. It is tightly controlled by cyclins, cyclin-dependent kinases (CDKs), and their downstream target, retinoblastoma protein (Rb). Dramatic clinical data seen recently with the small-molecule CDK4/6 inhibitor palbociclib (PB-0332991) targeting estrogen receptor (ER)-positive breast cancer, which accounts for 75% of all breast cancers, has rekindled interest in the concept of blocking cell cycle progression to stop cancer cell growth. In this regard, we tested the efficacy of the multikinase CDK inhibitor, PHA-848125 in breast cancer. Cell proliferation assays after PHA-848125 treatment of a large panel of breast cancer cells showed a reduction in the growth rate exclusively in ER-negative breast cancer cell lines, but not ER-positive cell lines. As a result of the CDK2 inhibitory activity of the drug, cell cycle analysis revealed a specific G1 arrest with a concomitant reduction of the phosphorylation of Rb. Inhibitory activity of the drug was also observed in vivo by treatment of ER-negative MDA-MB-231 xenotransplanted tumors with 40mg/kg of PHA-848125 twice a day, 5 days a week, for three weeks. Interestingly, repeated cycles of treatment did not induce resistance to the drug, which is the main reason of failure of many chemotherapies. Finally, treatment with PHA-848125 for 10 days of MMTV-PyVT transgenic mice that developed multifocal mammary adenocarcinoma and lung metastatic lesions showed tumor growth inhibition and a strong reduction in metastasic colonization of lungs. The results were further confirmed by orthotopic transplantation of MDA-MB-231 in NOD-SCID mice. Overall, these experiments demonstrated that PHA-848125 specifically target ER-negative breast cancer both in vitro and in vivo. Our report of the first targeted therapy for the ER-negative subtype lays out the rationale for the clinical evaluation of PHA-848125 in therapy for breast cancer.

Keywords: CDK inhibitor, PHA-848125, breast cancer